Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7][NH:6]1)=[O:4]>C1(C)C=CC=CC=1.O1CCOCC1.C1COCC1.O=[Mn]=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)C1Cc2cc(OC)c(OC)cc2CN1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Yield: 25.9 %

Procedure:
1.8 g (6.26 mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester and 3.3 g (37.6 mmol) of MnO2 in toluene/dioxane/THF was heated under reflux overnight. After gravity filtration, the hot filtrate was evaporated to produce 0.4 g (1.62 mmol, 26%) of 6,7-dimethoxy-isoquinoline-3-carboxylic acid methyl ester. LCMS: 248 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].C(N([CH2:16][CH3:17])CC)C.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20]>C(Cl)Cl>[F:1][C:2]1[C:3]([N:10]([S:21]([CH2:18][CH2:16][CH3:17])(=[O:23])=[O:22])[S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8]
Reactant: CCN(CC)CC
Reactant: Nc1ncc(F)c(I)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ncc(F)c(I)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3,5-difluoro-4-iodopyridin-2-amine (200 mg, 0.78 mmol) and triethylamine (240 mg, 2.34 mmol) in DCM (10 ml) at 0° C. was added n-propanesulfonyl chloride (0.28 g, 1.95 mmol). The mixture was allowed to warm to rt and was stirred for 2 h. It was then concentrated to provide the crude product, which was used in the next step without purification. MS m/z 469.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:9].Cl>CN(C=O)C.O>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH3:9]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)COCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCCCCNS(C)(=O)=O
Temperature: 100 °C
Yield: 17.1 %

Procedure:
To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5 mL). The mixture was heated at 100° C. for 1.5 h and was cooled to room temperature. A solution of (4-bromo-butoxy)-acetic acid ethyl ester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction was heated at 100° C. for 21 h. Water was added to the cooled reaction mixture and the aqueous solution was acidified to pH=2 with concentrated HCl. The aqueous solution was extracted with EtOAc (4×) and the organic solution was dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography (60% EtOAc/hexanes) to afford the title compound (181 mg). 1H NMR (400 MHz, CDCl3) δ 4.90 (m, 1H), 4.20 (q, 2H), 4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H), 1.26 (t, 3H); MS 254.1 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:9].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][C:32](O)=[O:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:29][CH2:28]2)[CH2:11]1)=[O:9]
Reactant: COC(=O)CCNC(=O)C1CCCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)C1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
To a mixture of N-[(3-piperidyl)carbonyl]-β-alanine methyl ester hydrochloride (1.57 g),3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid (1.61 g) and 1-hydroxybenztriazole (0.96 g) in N,N-dimethylformamide (16 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.14 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (CHCl3:MeOH 100:1) to give N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine methyl ester as an oil (2.19 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 180 °C
Yield: 17.3 %

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.0 g (0.040 mol) of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 180° C. for two hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 1.8 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 278-280° C. after recrystallization from pyridine.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:10][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(C)=O>[I-:2].[CH2:3]([O:10][C:11]1[C:15]([C:16]2[CH:17]=[N+:18]([CH3:1])[CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: c1ccc(COc2nsnc2-c2cccnc2)cc1
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nsnc2OCc2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(3-benzyloxy-1,2,5-thiadiazol-4-yl)pyridine (673 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.75 g (73%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:30])[N:25]=[C:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1.CC(C)=O>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:10](=[CH:9][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:30])[N:25]=[C:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:7][CH:6]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 70 mg, 0.160 mmol) and THF (1.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (30.6 mg, 0.160 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜3 mL of acetone yielding 58% (56.7 mg, 0.093 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>CN(C)C(=O)C>[CH:29]1([C:32]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[CH:6][N:5]3[CH:28]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Yield: 31.3 %

Procedure:
In the same manner as in Example 9-2 and using N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (300 mg, 0.797 mmol), cyclopropanecarbonyl chloride (72.0 μL, 0.797 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (111 mg, 31%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[C@@H:17]([CH:18]([OH:36])[CH:19]([NH2:35])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH2:16][O:15][C@@H:14]([O:37][CH2:38][C:39]2([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]1[C@@H:17]([C@@H:18]([OH:36])[C@@H:19]([NH:35][C:1](=[O:3])[CH3:2])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH2:16][O:15][C@@H:14]([O:37][CH2:38][C:39]2([CH3:44])[CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1(CO[C@H]2CN(C(=O)OC(C)(C)C)[C@@H](C(O)C(N)Cc3cccc(OCc4ccccc4)c3)CO2)CCCC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(OCc2ccccc2)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
Add acetyl chloride (0.13 mL, 1.82 mmol) to an ice cold solution of (2R,5R)-5-[2-amino-3-(3-benzyloxyphenyl)-1-hydroxypropyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.91 g, 1.652 mmol) and N,N-diisopropyl-ethylamine (0.58 mL, 3.30 mmol) in dichloromethane (20 mL). Stir 15 minutes and dilute with ethyl acetate and wash with 1 N hydrochloric acid, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, elutin with dichloromethane/ethyl acetate) to give the desired compound (246 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[OH:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([OH:18])[CH:17]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Oc1cc(O)cc(F)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(O)cc(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
Dimethylformamide (12.7 g) was added to vigorously stirred phosphorous oxychloride (14.4 g) at 0° C. The reaction mixture was stirred at this temperature for 30 minutes, then 3,5-dihydroxyfluorobenzene (6 g) was added. The sticky red syrup was allowed to warm to room temperature and stirred for 2 hours, then left to stand for 14 hours. Water (100 ml) was added and the mixture extracted three times with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2, v/v). Fractions homogeneous in the required product were combined and evaporated to give an orange solid which was triturated with ethyl acetate to give the title compound (2 g) as a yellow solid.
Reaction SMILES: C(C1(C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(O)=O)NC(C(OCC2C=CC=CC=2)=[O:14])C2(CCNCC2)S1)C1C=CC=CC=1.[CH:52]([N:55]=[C:56]=[N:57][CH:58]([CH3:60])[CH3:59])([CH3:54])[CH3:53].ClCCl.[N+](C)([O-])=O>C(Cl)(Cl)Cl>[CH:52]([NH:55][C:56]([NH:57][CH:58]([CH3:60])[CH3:59])=[O:14])([CH3:54])[CH3:53]
Reactant: O=C(OCc1ccccc1)C1NC(Cc2ccccc2)(C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)SC12CCNCC2
Reactant: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CC(C)NC(=O)NC(C)C
Reaction time: 12 h

Procedure:
The reation between 8 benzyl-4-benzyloxycarbonyl-alpha- tritylamino-1-thia-3,8-diazaspiro[4.5 ]decane-2-acetic acid (obtained in 6.2.) and diisopropylcarbodiimide (80 g) can be performed in chloroform (400 ml), dichloromethane or a mixture of nitromethane and chloroform, either at ambient temperature, leaving the mixture to stand for 4 weeks, or at 50° C. for 12 hours. In all cases, the 1,3-diisopropylurea formed is removed by filtration, the solvent and excess reagent are evaporated and the residue is passed through a column of silica gel (60 Merck), using chloroform as eluent. In all cases, benzyl 1°-benzyl-6-tritylamino-spiro[penam-2,4'-piperidine ]-3-carboxylate is obtained, which is crystallized from diethy ether in a yield of 25 to 40%; M.P. 191°-192° C. (recrystallized from acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-])=O)[C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.[H][H].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.Cl>O=[Pt]=O.C(O)C>[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:11][C:9]3[C:8](=[CH:7][C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)[N:14]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccncc1
Reactant: [H][H]
Reactant: Cn1cnc2cc([N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: Cn1cnc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
4.40 g. (20.0 mMole) 1-methyl-5,6-dinitrobenzimidazole and 0.5 g. Adams catalyst in 250 ml. ethanol are hydrogenated for 4 hours at 40° C. and 4 bar hydrogen pressure. The catalyst is filtered off and the filtrate, after the addition of 2.10 g. (20.0 mMole) pyridine-4-aldehyde and 3 ml. concentrated hydrochloric acid, is heated to the boil under reflux. After chromatographed purification (silica gel; ethyl acetate/methanol 1:1 v/v) and evaporation of the appropriate fractions, there is obtained 1.1 g. (21% of theory) of the desired product in the form of colourless crystals of the semihydrochloride; m.p.>280° C.
Reaction SMILES: P(Cl)(Cl)Cl.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:47](=[O:48])[N:16]2[C:17]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:18]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[C@@H:19]([CH3:22])[S:20](=O)[C@H:15]12)=[O:12].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:47](=[O:48])[N:16]2[C:17]([C:31]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[C:18]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[C@@H:19]([CH3:22])[S:20][C@H:15]12)=[O:12]
Reactant: C[C@@H]1C(CSc2nnnn2C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1CSc1nnnn1C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A 0.38 ml portion of PCl3 was added to a solution of 326 mg of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate 1-oxide in 5 ml of DMF at -10° C., followed by stirring at the same temperature for 15 minutes. AcOEt and 5% aqueous NaHCO3 solution were added to the reaction solution to separate out the AcOEt layer. The AcOEt layer was washed with saturated aqueous NaCl solution and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (25:1) were collected, followed by distilling off the solvent under reduced pressure, thus yielding 225 mg (71%) of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[C:18]([NH:17][C:14](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[S:13][CH3:12])#[N:19]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCSCc1ccccn1)NC#N

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85°-88°. (from isopropyl alcohol-ether)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41](=[O:49])[C@:42]([CH3:48])([CH2:44][CH2:45][S:46][CH3:47])[NH2:43].CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:43][C@@:42]([CH3:48])([CH2:44][CH2:45][S:46][CH3:47])[C:41]([O:40][CH3:39])=[O:49])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)c1
Reactant: COC(=O)[C@@](C)(N)CCSC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@](C)(CCSC)NC(=O)c1cccc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
To a mixture of 3-((E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl)benzoic acid (0.50 g, 1.55 mmol; prepared as the product of step D in Example 1), EDC (0.30 g, 1.55 mmol) and HOBt (0.21 g, 1.55 mmol) in dichloromethane (20 ml) was added α-methyl methionine methyl ester (0.33 g, 1.55 mmol) and 4-methylmorpholine (0.17 ml, 1.55 mmol). The solution was stirred at room temperature for 17 hrs, washed with brine (3×40 ml) dried over (MgSO4) and the solvent evaporated to leave a yellow gum. This was purified by chromatography (Biotage flash 40, 40 g SiO2 cartridge) eluting a gradient of 0-1% 0.88 aqueous ammonia/EtOAc to give the desired end product as a yellow gum 0.38 g (50%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH3:35])=[CH:23][N:22]=3)=[N:13]2)=[C:9]([Cl:36])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.[CH3:44][N:45](C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.C(N(C(C)C)C(C)C)C.CN>CS(C)=O.O1CCCC1>[Cl:1][C:2]1[C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH3:35])=[CH:23][N:22]=3)=[N:13]2)=[C:9]([Cl:36])[CH:8]=[CH:7][C:3]=1[C:4]([NH:45][CH3:44])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Cl)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2,4-dichloro-3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoic acid (19-1, 0.192 mmol, 1. eq.) were dissolved in 0.953 ml of dry dimethyl sulfoxide. 80.2 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1.1 eq.), 67 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.384 mmol, 2 eq.) and 96 μl of 2 N methyl amine in tetrahydrofuran were added in this sequence. The reaction mixture was stirred at room temperature for 18 hours. 80.2 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1.1 eq.), 67 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.384 mmol, 2 eq.) and 96 μl of 2 N methyl amine in tetrahydrofuran were added in this sequence again twice and stirred each time at room temperature for 24 hours. The reaction mixture was stirred at 50° C. bath temperature for further 2 hours. Then the mixture was filtered off purified by preparative HPLC to yield 15 mg (0.03 mmol, 14.3%) of the analytically pure target compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]3[C:13]4=[C:14]([F:22])[CH:15]=[N:16][C:17]5[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=54)[CH2:10]3)[CH2:4][CH2:3]2)=[O:36])=[CH:33][CH:32]=1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C[C@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1)c1ccc(Br)cc1
Yield: 87 %

Procedure:
A solution of 4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 2 (200 mg, 0.664 mmol) in dichloromethane (5 ml) was treated with triethylamine (0.139 ml, 1 mmol), ice-cooled under argon and treated with 4-bromobenzoyl chloride (150 mg, 0.682 mmol). The solution was shaken with excess aqueous sodium bicarbonate solution, separated and the aqueous re-extracted twice with 15% methanol/dichloromethane. The combined organic extracts were dried and evaporated and the residue chromatographed using dichloromethane/methanol/0.88 ammonia 96:4:0.4 to give 4-bromo-N-(1-{[(4S)-3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl}-4-piperidinyl)benzamide (280 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][CH2:18][NH2:19])[CH3:13].C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14][CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCOc1ccccc1CCN
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1CCNc1ccc2ncc(Br)n2n1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), 2-ethoxy-phenethylamine (1 g, 6 mmol) and triethylamine (1 ml) in isopropyl alcohol (2 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column), to gave the titled compound (980 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (t, J=6.95 Hz, 3H) 3.04 (t, J=6.69 Hz, 2H) 3.64-3.72 (m, 2H) 4.06-4.17 (m, 2H) 4.97 (br. s., 1H) 6.40 (d, J=9.60 Hz, 1H) 6.87-7.02 (m, 2H) 7.17-7.32 (m, 2H) 7.47 (s, 1H) 7.54 (d, J=9.60 Hz, 1H). LRMS (ESI) m/z 361 and 363.1 [(M+H)]+, calc'd for C16H17BrN4O: 361.24.
Reaction SMILES: [C:1](=[O:4])([O-:3])N.CNCCCCCC[N:13]1[C:17]2[CH:18]=[CH:19]C=C[C:16]=2[NH:15][C:14]1=O.FC(F)(F)C(O)=O.[NH2:30][C@@H](CC1CCCCC1)[C@@H](O)CN(C)CCCCCCN1C2C=CC=CC=2NC1=O>C(Cl)Cl>[NH2:30][C@H:19]([C:1]([OH:3])=[O:4])[CH2:18][C:17]1[N:13]=[CH:14][NH:15][CH:16]=1
Reactant: NC(=O)[O-]
Reactant: CN(CCCCCCn1c(=O)[nH]c2ccccc21)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CNCCCCCCn1c(=O)[nH]c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
This compound was prepared, likewise in analogy to Examples 1 and 2, by reacting t-butyl [(1S,2R:S=9:1)-1-(cyclohexylmethyl)-2,3-epoxypropyl]carbamate with 1-[6-(methylamino)hexyl]-2-benzimidazolinone, cleaving off the Boc protecting group with 90% trifluoroacetic acid in methylene chloride and reacting the 1-[6-[[(2S,3S)-3-amino-2-hydroxy-4-cyclohexylbutyl]methylamino]hexyl]-2benzimidazolinone obtained with 1-(t-butoxycarbonyl)-N-(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine.